Genes, environment, and chance determine the course of human aging. This project focuses on the genetic contributions to longevity and healthy aging. Longevity is the phenotype we will use in this analysis, but it will be combined with functional outcome measures, to address hypotheses relating to the role of metabolism in aging. Associative genetics is the initial tool we will use. It will be applied to candidate genes that have been validated in model organisms as longevity genes, starting with HRAS1, LASS1, IGFIR, PPARG, and PRKAA2, followed by others. Genes such as APOE and LEPR are of particular interest in other projects of this Program Project, and they will be studied as well. All of the genes are involved in metabolism and stress resistance. Partial genomic scans will also be applied in this analysis, in particular in regions of the genome that are syntenic to mouse genome regions implicated in robust immune function coupled to longevity. The analysis will begin with an assessment of the genetic structure of our population in the genomic regions of interest, followed by a comparison of the level of variation in nonagenarians and younger controls. Next, we will test the detected variation in other populations, both non-preselected for age and age-selected (i.e. replication in other Iongevous cohorts). We will also apply a panel of ethnic affiliation markers to control for the confounding effects of population admixture. This analysis, in conjunction with the tests in other populations, may suggest the existence of Iongevous haplotypes in our population. This possibility will be explored further by searching for such haplotypes. Finally, we will examine the functional significance of any allelic variants detected at higher frequency in nonagenarians. This will be done by studying the effects on life span of homologous mutations using the yeast model system. It will also involve assays of antigen-induced T-cell death and transient transfection assays of transcription activity. The inclusion of this genetic study in the context of this Program Project with its focus on metabolism and functional outcome measures will help elucidate the attributes of healthy aging, and it provides the perspective of improvement of the quality of life in old age.